Isoquinolines are very well-known in the chemical literature. For example, the synthesis of isoquinolines has been comprehensively reviewed [Kametani et al.; The Chemistry of Heterocyclic Compounds, Isoquinolines, Vol. 38, Part 1, Chap. 2, J. Wiley & Sons, 1981, p. 139-274].
U.S. Pat. No. 3,912,740, issued to Zee-Cheng et al. on Oct. 14, 1975, discloses among others compounds of the formula ##STR1## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently are H, alkyl of 1 to 6 carbon atoms, or benzyl with the proviso that R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 taken together represent methylene;
R.sup.5 is alkyl of 1 to 6 carbon atoms; PA0 R.sup.6 is H or alkoxy of 1 to 6 carbon atoms; and X is an anion. PA0 R.sup.2 is H, CH.sub.3, or Cl; PA0 R.sup.3 is R.sup.5, Cl, N(R.sup.5).sub.2, or N.sup.+ (R.sup.5).sub.3 I.sup.- provided that, if X is NR.sup.6 R.sup.7, R.sup.3 is not N(R.sup.5).sub.2 or N.sup.+ (R.sup.5).sub.3 I.sup.- ; PA0 R.sup.4 is H, CH.sub.3, or Cl; PA0 R.sup.5 is H, or C.sub.1 to C.sub.3 alkyl; PA0 X is O, or NR.sup.6 R.sup.7 ; provided that, if X is O, a is a single bond, b is a double bond, and Y is NH, and, if X is NR.sup.6 R.sup.7, a is a double bond, b is a single bond, and Y is N; PA0 R.sup.6 and R.sup.7 independently are R.sup.5, (CH.sub.2).sub.n N(R.sup.5).sub.2 where n is 2 to 8, or R.sup.6 and R.sup.7 taken together represent --(CH.sub.2 CH.sub.2).sub.2 NR.sup.5 ; PA0 R.sup.1 is H; PA0 R.sup.2 is H or CH.sub.3 ; and PA0 R.sup.4 is H. PA0 (a) (Ex. 1) R.sup.1 =R.sup.2 =R.sup.3 =R.sup.4 =H and X=O; 3-(1-naphthalenyl)-1(2H)-isoquinolinone. PA0 (b) (Ex. 2) R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =Cl and X=O; 7-chloro-3-(1-naphthalenyl)-1(2H)-isoquinolinone. PA0 (c) (Ex. 3) R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =CH.sub.3 and X=O; 7-methyl-3-(1-naphthalenyl)-1(2H)-isoquinolinone. PA0 (d) (Ex. 4) R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =N(CH.sub.3).sub.2 .multidot.HCl and X=O; 7-(dimethylamino)-3-(1-naphthalenyl)-1(2H)-isoquinolinone hydrochloride. PA0 (e) (Ex. 20) R.sup.1 =R.sup.3 =R.sup.4 =H; R.sup.2 =CH.sub.3 and X=NH.sub.2 ; 6-methyl-3-(1-naphthalenyl)-1-isoquinolineamine. PA0 (f) (Ex. 21) R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =Cl and X=NH.sub.2 ; 7-chloro-3-(1-naphthalenyl)-1-isoquinolineamine. PA0 (g) (Ex. 31) R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =CH.sub.3 ; and X= ##STR4## 7-methyl-1-(4-methyl-1-piperazinyl)-3-(1-naphthalenyl)-isoquinoline. (h) (Ex. 40) R.sup.1 =R.sup.2 =R.sup.4 =H; R.sup.3 =CH.sub.3 ; and X=N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 ; N,N,N'-trimethyl-N'-(7-methyl-3-(1-naphthalenyl)-1-isoquinolinyl)-1,2-etha nediamine.
These compounds are disclosed as having activity against murine L1210 leukemia and murine P388 leukemia.
U.S. Pat. No. 4,014,885, issued to Zee-Cheng et al. on Mar. 29, 1977, discloses compounds of the formula ##STR2## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 independently are H, alkyl of 1 to 6 carbon atoms, or benzyl, with the proviso that R.sup.1 and R.sup.2 taken together represent methylene.
Poindexter [J. Org. Chem., 47, 3787-3788 (1982)] reports the synthesis of 1(2H)-isoquinolinones by the reaction of the dilithium species derived from N,2-dimethylbenzamide with organic nitriles. No use for these compounds is described. Rose et al. [J. Chem. Soc. (C) 2205-2208 (1968)] reports the synthesis of 1(2H)-isoquinolinones by the reaction of ammonia with 3-arylisocoumarins. No use for these compounds is described.
The 1(2H)-isoquinolines of Formula (I) wherein X is O are prepared by a similar method involving the reaction of the monolithium species derived from substituted N,N,2-trimethylbenzamides with 1-cyanonaphthalene.
Pijper et al. [Eur. J. Med. Chem.-Chim. Ther. 19, 389-392 (1984)] and de Zwart et al. [J. Med. Chem. 31, 716-722 (1988)] report the synthesis and antimycoplasmal activity of 3-(2-pyridyl)-1-isoquinolineamines. Kaiser et al. [Synthesis, 805-806 (1974)], Van der Goot et al. [Eur. J. Med. Chem.-Chim. Ther. 10, 603-606 (1975); Eur. J. Med. Chem.-Chim. Ther. 7, 185-188 (1972)], and Wijbe in GB 1,173,227, issued on Dec. 3, 1969, report the synthesis of 1-isoquinolineamines by the reaction of the metalated species derived from 2-methylbenzonitrile with organic nitriles. This general method is used to prepare the compounds of this invention of Formula (I) wherein X is NH.sub.2.
There are no known literature references disclosing the compounds of this invention or their use in the inhibition of mammalian tumors.
The compounds of this invention have in vitro and in vivo anticancer activity. As shown in Table 7, the compounds of this invention inhibit the growth of the RPMI-7272 human colon tumor cell line with ID.sub.50 's ranging from 0.00077 .mu.g/mL to 0.95 .mu.g/mL. As shown in Tables 3 to 6, the compounds of this invention have significant anticancer activity in vivo in the L1210 murine leukemia, P388 murine leukemia, B16 murine melanoma, and/or LOX human amelanotic melanoma models.